tbuckley/cabot-search huggingface dataset:
P02.19.A ASSESSMENT OF HEAT SHOCK PROTEIN HSP70 EXPRESSION IN THE GLIOBLASTOMA STEM-LIKE CELLS
Authors: M Shevtsov, N Yudintceva, A Nechaeva
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by poor prognosis. The search of biomarkers for early diagnosis and as targets and for tumor theranostics due to the aggressiveness of the disease is urgently needed. One of the promising targets for therapy of brain tumors is 70 kDa heat shock protein (Hsp70), which has been found on the plasma membrane of various tumor cells (including GBM) but not on normal cells. GBM, like other types of tumors, has cellular heterogeneity. In particular, it contains tumor stem-like cells (TSLCs), which are considered analogues of healthy stem cells and are largely responsible for disease progression, recurrence and mediate resistance to ongoing therapy. In the present work, the histological sections of human GBM were analyzed to identify and quantify the colocalization of the heat shock protein Hsp70 with TSLC markers using the Opal Multiplex analysis system. MATERIAL AND METHODS Histological sections were prepared in accordance with the standard protocol using postoperative material from patients with newly diagnosed GBM (n=15). Zones of necrosis and living tissue were identified on tumor sections. Based on a phenotyping map using the Pathology Views™ fluorescence image analysis software, Hsp70 colocalization was quantified with Nestin and Sox2 in the areas of necrosis and viable tissue employing primary antibodies (anti-Hsp70, anti-Nestin and anti-Sox2). The preparations were stained using an Opal 3-Plex Manual Detection Kit according to the manufacturer's protocol. RESULTS The expression of Hsp70 and TSLC markers (Nestin and Sox2) was detected. The obtained quantitative data did not reveal significant differences in the distribution of cells expressing Hsp70 in the areas of necrosis and viable tissue (36 and 41%, respectively), which may indicate their uniform distribution in the tumor. Sufficiently high colocalization of Hsp70 with Nestin and Sox2 factors was detected mainly in the zone of viable tissue (57 and 30%, respectively). CONCLUSION Colocalization of Hsp70 with TSLC markers indicates the prospects for further studies of Hsp70, as well as its use for targeted therapy of malignant brain tumors.
P11.79.B MULTICENTRE MULTI-COMPONENT DATA COLLECTION TO DEFINE NEW PREDICTORS OF RELAPSE IN HIGH GRADE GLIOMA
Authors: L Mrissa, C Satragno, M Savanovic, Y Karakaya, C Yuste, C Veres, K Sambourg, L Dautun, T Hachemi, V Cifliku, A Le, P Meyer, C Jenny, J Jacob, A Bombezin Domino, P Maingon, S Bockel, F Dhermain, G Noël, E Deutsch, C Robert
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The aim of our multi-centric study is to evaluate the predictive relapse factors for high-grade glioma patients. MATERIAL AND METHODS We studied retrospectively multi-centric cohort of high-grade glioma patients, from 2009 to 2021 at three French medical centers. This data collection was carried out as part of national funding to promote the integration of AI tools into clinical oncology routine (AI.DReAM project). Clinical, pathological, genomic, and radiotherapy data, with MR images before treatment and at relapse, were collected and are being analyzed.Relapse patterns were separated into radiotherapy and radiological-related patterns. The latter were defined based on T1-gadolinium and FLAIR sequences. We distinguished local and disseminated disease. We then sub-categorized into residual growth, new local or distal lesion, multi-focal and multi-centric relapse.We underwent a uni-variate analysis with the Chi-squared test and a multivariate analysis with logistic regression to find multi-centric relapse-related factors. RESULTS Overall, 976 files were collected. In this preliminary analysis, we evaluated data from 203 patients. Out of the latter, 70% were male. 28% of the patients were aged more than 69 years. 43% of patients underwent Gross Tumor Resection, and 36% had only biopsy. Considering that of 20,7% of patients underwent Subtotal Tumor Resection, less than 10% had a resection of more than 90%.23% of patients had multi-focal disease and 16,7% had multi-centric disease. 54,6% had temporal disease making it the most frequent site, 26,6% of patients had a deep location. Ventricular contact was noted in 58% of the cases. MGMT methylation was noted in 34% of the patients.The median radiation dose received was 60Gy [33Gy-72Gy]. 98,5% of patients received Temozolomide with radiation and 80% continued it in the adjuvant setting.The median progression-free survival was 7 months, and the median overall survival was 17,6 months [3 to 92 months].The univariate analysis showed a correlation between multi-centric or bilateral initial disease and multicentric relapse pattern (p=0.015 and p=0.012 respectively). The multivariate analysis showed no correlation between our data and the multi-centric relapse. CONCLUSION The preliminary results of our study did not find an association between the analyzed data and the multi-centric relapse pattern.The challenge set is ambitious, as there are no studies yet that identify the factors associated with the multi-centric relapse pattern.Further analyses, currently in progress, are needed for the cohort of 976 patients, taking into account disease and radiotherapy volumes. The final results will be presented at the congress
P02.17.A FEATURES OF METABOLIC PSEUDO-PROGRESSION VISUALIZATION OF GRADE 3-4 GLIOMAS AFTER COMBINATION THERAPY. CORRELATION WITH MRI
Authors: A Smirnova, E Gromova, N Plakhotina, M Anishkin, A Smirnova
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Follow-ap assessment of post-therapeutic changes in gliomas of 3-4 raids revealed the phenomen of metabolic pseudoprogression. This feature was manifested in a transistor increase in the capture of the radiopharmaceutical. This "anomaly" requires study for a correct differential diagnosis between progression and pseudoprogression MATERIAL AND METHODS For the period from 2019 to 2023, 27 patients aged 24-72 years (average age 55 years) with the phenomena of metabolic pseudoprogression of 3-4 grades gliomas after combination therapy participated in the study. The studies were carried out using PET-CT and 1.5T, 3.0T MR scanners using T2, T2 flair, T13D before and after contrast, T2* perfusion. Postprocessing was carried out using a workstation SINGO.VIA using technological processes: neuro3d, MM oncology, MR neurology. RESULTS It was found that in all cases of transient increase in radiopharmaceuticals capture after radiotherapy in terms from 9 months to 36 months, the values of radiopharmaceuticals accumulation were determined in the range of 1.8-3.5 and were they were divided into two groups according to MRI data: group A (n=17) with structural changes, group B (n=10) with a stable MR pattern. According to MRI data in group A, there was an increase in the pathological zone, these changes involved white matter with more pronounced changes in the periventricular regions. In group B, the changes concerned gray matter. In addition, changes in group B were accompanied by manifestations of vasculopathy of the SMART type (Stroke-Like Migraine Attacks After Radiation Therapy). In subsequent observations, these changes in both groups were reduced, both according to PET and MRI CONCLUSION A temporary increase in the values of the capture of radiopharmaceuticals after combination therapy for high grade gliomas can be determined both in the white and gray matter of the brain. This may correspond to the manifestations of a post-radiation reaction. Compared with the MRI data, there is a difference in morphological manifestations at the level of gray and white matter, which is probably due to their different radioresistance. These newly discovered factors may be of key importance for further treatment of patients
P10.34.B ONCOGENIC ASPP2KAPPA(K), A DOMINANT-NEGATIVE ISOFORM OF THE APOPTOSIS STIMULATING PROTEIN OF P53-2 (ASPP2) PROMOTES CLASSICAL HALLMARKS OF CANCER IN GLIOBLASTOMA
Authors: M Hafner, A Ruiba, L Kampa, I Sommer, A Ahrens, V Kälin, A Zeitlberger, K Buchauer, L Plasswilm, T Hundsberger, M Neidert, M M Schittenhelm, K M Kampa-Schittenhelm
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND GB is the most common, most aggressive primary brain tumor with a deleterious prognosis. ASPP2 is a tumor suppressor, directly interacting with p53. We recently identified a dominant-negative isoform of ASPP2, named ASPP2κ, lacking the important p53 binding sites and show that ASPP2κ is highly expressed and functionally active in glioblastoma, affecting all classical hallmarks of cancer. MATERIAL AND METHODS Grade IV glioma (n=46) were assessed for ASPP2κ expression. Isogenic GB models, stably suppressing or overexpressing ASPP2κ, were established in A-172, U-251 and T98g cell lines and from resected GB tissue. The role of ASPP2κ in induction of apoptosis, cellular proliferation, migration and invasion was assessed in vitro and in vivo. Proteome arrays allowed to study pathways involved in ASPP2κ signaling. Two ASPP2κ knock-down (KD) NOD/SCID xenotransplant mouse models were established to study ASPP2κ in tumor engraftment and progression. RESULTS Frequent overexpression of ASPP2κ was confirmed in virtually all patients analyzed compared to tumor-free tissue. Expression thereby varied widely in between patients (2-40 fold). Functional analyses confirm that ASPP2κ directly affects multiple cancer hallmarks in GB, resulting in a more aggressive phenotype with impaired induction of apoptosis (avg. -25 %), higher proliferation (avg. +25%), migration (avg. +65%) and invasion (avg. +70%) rates. Silencing of ASPP2κ rescues the ASPP2 wt tumor suppressor phenotype, rendering cells more susceptible towards temozolomide (TMZ, avg. +25%), γ-irradiation (avg. +40%) or combinational approaches. Upregulation of p53 phosphorylation sites (S15: 2,5x/S46: 1,5x) and cell cycle regulators (p21: 2x, p27: 3x and pRAD: 2,5x) thereby confirms restoration of important p53-mediated pathways. GB mouse models confirm attenuated tumor engraftment and progression of ASPP2κ KD tumors in vivo. Mice carrying ASPP2κ-KD tumors presented with statistically significant increased overall survival in both models (p= 0.03 and p=0.005) and attenuated tumor growth (p=0.0001). Importantly, neo-angiogenesis was strongly regulated in relation to ASPP2κ expression, impairing tumor growth and metastasis in the ASPP2κ KD models. Downregulation of pro-angiogenic (VEGF 20x, angiogenin 4x) and upregulation of anti-angiogenic (endostatin 2x, LAP 2,5x) players in ASPP2κ KD models were confirmed. CONCLUSION ASPP2κ is highly expressed in GB, affecting all classical hallmarks of cancer, including regulation of apoptosis, cell cycle, invasion/metastasis and angiogenesis. ASPP2κ contributes to aggressiveness of disease and resistance to therapy and silencing of ASPP2κ re-activates crucial p53-mediated tumorsuppressor pathways. Studies evaluating ASPP2κ as a target for therapy are ongoing.
P11.75.B PSEUDOPROGRESSION IN A REAL-WORLD GLIOBLASTOMA COHORT: INCIDENCE, MANAGEMENT, PROGNOSTIC IMPACT, AND ASSOCIATED FACTORS
Authors: H Blakstad, E E Mendoza Mireles, L C Heggebø, H Magelssen, M Sprauten, T B Johannesen, E Vik-Mo, H Leske, P Niehusmann, K Skogen, E Helseth, K E Emblem, P Brandal
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Radiotherapy remains a cornerstone in glioblastoma (GBM) management. A continued and unmet need in neuro-oncology is efficient non-invasive methods to differentiate post-radiation magnetic resonance imaging (MRI) changes from progressive disease (PD) in GBM patients. The clinical challenge is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed incidence, management, prognostic impact, and associated factors with PsP in a real-world GBM patient cohort. MATERIAL AND METHODS Adult (≥18 years) GBM patients diagnosed in the South-Eastern Health Region of Norway from 2015 to 2018, had received radiotherapy, and follow-up MRIs were included. Patient, tumor, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at three and six months post-radiation using response assessment in neuro-oncology criteria. RESULTS PsP incidences at three and six months post-radiation were 20% and 8%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and absence of neurological deterioration were associated with PsP at both three (p&amp;lt;0.001 and p=0.04, respectively) and six months (p=0.003 and p=0.04, respectively) post-radiation. Patients with PsP at MRI three months post-radiation had a median OS of 24.8 months compared to 11.4 months for patients with PD and 18.7 months in patients with stable disease (SD); the difference was significant only when comparing patients with PsP and PD (p&amp;lt;0.001). There was no survival benefit of treatment change for patients retrospectively evaluated as PD three months post-radiation (p=0.8). Median OS for patients in the PsP group was 31.8 months and thus longer than in the PD group (13.1 months) and the SD group (24.1 months). The difference was only significant when comparing patients with PsP and PD (p&amp;lt;0.001). CONCLUSION PsP incidence in this retrospective material was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that the absence of neurological deterioration significantly correlated to PsP. Continuation of temozolomide courses did not compromise survival for patients with PD at three months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings. Funding: European Union's Horizon 2020 Programme European Research Council Grant 758657-ImPRESS.
P06.12.A NLGN4X-SPECIFIC TCR T CELLS TARGETING EXPERIMENTAL GLIOMAS
Authors: C Krämer, M Kilian, Y Chih, A Kourtesakis, T Boschert, K Sanghvi, A de Roia, S Jung, K Jähne, L Shultz, R Harbottle, E Green, R Will, W Wick, M Platten, L Bunse
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A human leukocyte antigen (HLA)-A*02-restricted tumor associated antigen in the neuroligin 4 X-linked (NLGN4X) protein was found to be specifically overexpressed in human gliomas. Individualized multipeptide vaccination targeted NLGN4X and induced specific cytotoxic T cells responses in patients with newly diagnosed glioblastoma. MATERIAL AND METHODS Post vaccination NLGN4X-tetramer-sorted T cells were subjected to single cell T cell receptor (TCR) sequencing for TCR discovery. The identified TCR was delivered to human T cells (NLGN4X-TCR-T) and functional profiling was performed by flow cytometry and in vitro cytotoxicity assays. NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) (NSG MHC I/II KO) mice were challenged with NLGN4X-expressing experimental gliomas and treated with intracerebroventricular injection of NLGN4X-TCR-T to assess its therapeutic potential. RESULTS We apply for the first time for therapeutic use of an HLA-A*02 restricted vaccine-induced TCR that binds to the NLGN4X antigen. We show the cytotoxic and polyfunctional phenotype of NLGN4X-TCR-T in various cellular models. Intracerebroventricular delivery of NLGN4X-TCR-T prolongs survival and leads to objective radiographic responses in experimental gliomas-bearing NSG MHC I/II KO mice. CONCLUSION NLGN4X-TCR-T demonstrates efficacy in a preclinical experimental glioblastoma model. On a global scale, we provide first evidence for the therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf treatment of glioblastoma patients.
JS09.8.A COMPARATIVE PROGNOSTIC VALUE OF O-(2-[18F]-FLUOROETHYL)-L-TYROSINE PET IMAGING AND DCE MRI BLOOD VOLUME IMAGING IN PATIENTS WITH SUSPECTED RECURRENT IDH-WILDTYPE HIGH-GRADE GLIOMA
Authors: O M Henriksen, A Muhic, M J Lundemann, H B W Larsson, U Lindberg, T L Andersen, B Hasselbalch, S Møller, L Marner, V A Larsen, H S Poulsen, A E Hansen, I Law
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Quantitative blood volume (BV) imaging using dynamic T1-weighted contrast enhanced (DCE) perfusion MRI may be of diagnostic value in patients with suspected recurrent high-grade glioma, but the association of DCE BV measurements with survival is not known. The aim of the study was to compare the prognostic information of DCE BV measurements with that of O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET imaging in treated IDH wildtype high-grade astrocytoma and glioblastoma (2016 WHO classification). MATERIAL AND METHODS A total of 94 hybrid [18F]FET PET/MRI scans with DCE from unique adult patients were retrospectively analysed. Scans were obtained after surgery/biopsy (n=94) and radiotherapy (n=93) due to variable suspicion of residual or progressive disease. In each scan the visually BV positive (VOLBV), the [18F]FET PET avid (VOLFET) and the contrast-enhancing (VOLCE) volumes were delineated, and fractional tumour volumes (fVOL) within VOLCE, as well as maximal BV (BVmax) and maximal [18F]FET tumour-to-background ratio (TBRmax) were determined. Accuracy for prediction of 6-month progression free survival and 1 year overall survival were assessed by logistics regression. Associations with overall survival were assessed for each parameter by Cox proportional hazard analysis. RESULTS In a univariate analysis, adjusted for age and MGMT, both VOLCE, and all [18F]FET and DCE BV derived metrics were predictive of both 6 month progression free survival, 1 year survival and overall survival. ROC AUC for prediction of 6 month progression free survival and 1 year overall survival tended to be higher for [18F]FET derived metrics, but ROC AUC values were not significantly different between any [18F]FET and DCE BV derived metrics. In Cox models for overall survival (adjusting for age, MGMT and VOLCE) only TBRmax and VOLBV had independent prognostic value among [18F]FET PET and DCE BV derived metrics, respectively. In a final model including both TBRmax and VOLBV, only TBRmax remained significant.. CONCLUSION DCE BV and [18F]FET PET derived metrics provides prognostic information independent of age, MGMT status and contrast enhancing tumour volume in treated glioblastoma, with volume of increased BV and [18F]FET TBRmax providing strongest associations with overall survival. Accounting for functional imaging biomarkers may be important in balancing future randomized clinical trials.
OS09.2.A REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2, EUDRA CT N° 2021-001604-15)
Authors: M Padovan, G De Salvo, G Cerretti, M Krengli, M Caccese, M Maccari, M Farina, E Bergo, C Zabeo, D Grosso, F Caumo, M Coppola, A D'Avolio, V Zagonel, G Lombardi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is associated with the activation of multiple signaling pathways, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the phase II REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneous xenografts. MATERIAL AND METHODS This phase I open-label multicentric study in progress is evaluating the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ + radiotherapy (RT) as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in these two cohorts. Secondary objectives are: the assessment of pharmacokinetics of REG, TMZ, and possible pharmacokinetic interactions between TMZ and REG in cohort A; the assessment of preliminary antitumor activity; the evaluation of quality of life during the treatment. The dose escalation is being explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ + RT (60 Gy/30 fractions). In the adjuvant phase of cohort B, REG will be given with TMZ at MTD shown in the prior adjuvant phase dose escalation.The DLT (dose-limiting toxicity) evaluation period will be two cycles from the start of cycle 1 of adjuvant phase (in cohort A) and from day 1 to the last day of the concomitant phase (in cohort B). Recruitment started in May 2022; Level 1 in cohort A (3 patients) has been completed without DLT. Approximately 36 subjects will be enrolled.
P11.39.B PREDICTING RESPONSE TO CHEMOTHERAPY IN RECURRENT HIGH GRADE GLIOMAS USING<i>EX VIVO</i> 3D CELL CULTURE FUNCTIONAL PRECISION ONCOLOGY PLATFORM
Authors: M M Mrugala, R Zimmerman, D Greene, S Fortin-Ensign, M Blomquist, K Swanson, B Bendok
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Treatment of recurrent high-grade glioma remains a clinical challenge. There are very few agents active in this disease and short of enrollment in a clinical trial, the choice of therapy for a patient at the time of recurrence remains challenging. Several groups, including our own have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. To our knowledge, there is only one commercially available platform from the US based company Kiyatec. This tool, in addition to the molecular analysis of the tumor might provide another layer of confidence in choosing treatments for patients with recurrent high-grade gliomas. MATERIAL AND METHODS We present the data from our initial experience with the 3D PredictTM platform (Kiyatec, Greenville, SC, USA). We used the platform for 6 patients with recurrent high-grade gliomas undergoing tumor resection at the time of recurrence. We followed the company protocol for obtaining, preserving and shipping the tissue. RESULTS Out of the 6 specimens shipped for analysis, 4 assays were completed with full results available for analysis and clinical use. In two cases, the ex vivo tissue expansion was unsuccessful and drug testing was not completed. For the remaining 4 cases, spheroids created from the expansion of the harvested tissue were exposed to 12 drugs (temozolomide, lomustine, procarbazine, abemaciclib, carboplatin, dabrafenib, etoposide, everolimus, irinotecan, osimertinib, rucaparib and trametinib). We have observed different levels of sensitivity to several agents graded as: NO RESPONSE, MODERATE RESPONSE and RESPONSE. In 3 cases the results were used for clinical decision making and 2 patients were started on temozlomidede and carboplatin respectively and remain on treatment. In one case where sensitivity to etoposide was detected, we were not able to proceed with therapy due to insurance denial for the chosen drug. CONCLUSION In our experience, this platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for testing is high and the information derived from the drug sensitivity testing can be useful in clinical practice. Large, prospective clinical trial is need to validate this approach for routine clinical use.